Therapeutic agents see their efficiency intimately related to their method of administration. When taken orally, a drug interacts with specific absorption sites located in different portions throughout the gastrointestinal tract (GI), resulting in that certain agents are only absorbed in the stomach, the upper or lower intestine. Therefore, because the drugs are not absorbed uniformly all over the length of the GI tract, the rate of absorption may not be constant and does not allow a most efficient treatment. These may significantly be improved when the method of administration provides a controlled delivery of the active ingredient towards the only implicated sites.
For example, it may be significant to prolong the residence time specifically in the stomach in the case of drugs which are only locally active such as anti-acids, have an absorption window in the stomach or in the upper intestine such as L-Dopa or riboflavin, are unstable in the intestinal or colonic environment such as captopril or exhibit low solubility at high pH values such as diazepam, or verapamil. This may be also important in treatments of micro-organisms, which colonize the stomach since the three main factors reducing luminal delivery of drugs to them are gastric emptying, gastric acidity and the epithelial mucus layer. These forms may also be used to release a biomarker to monitor and identify gastric conditions.
While the existing immediate release forms provide the disadvantage of repeated administration of a medicament as well as fluctuations in drug plasma levels, controlled drug delivery systems were significantly developed. They allow the delivery of a therapeutic agent in such way that the level of the drug is maintained within a particular window as long as the form continues to deliver the drug at a constant rate. Also, apart from reducing the required frequency of administration or maintaining safe blood levels, there are other benefits associated with the intake of controlled release forms such as the reduction of the severity of side effects.
A large variety of controlled release forms have already been disclosed, as summarized in “Gastroretentive drug delivery systems”, by Alexander Streubel, Juergen Siepmann & Roland Bodmeier, Expert Opin. Drug Deliv. (2006) 3(2):217-233, or in “Gastroretentive dosage forms: Overview and special case of Helicobacter Pylori”, J. Control. Rel., 111 (2006) 1-18 by Bardonnet et al. They are based on different modes of operation and accordingly have been variously named, for example, as dissolution controlled systems, diffusion controlled systems, ion exchange resins, osmotically controlled systems, erodible matrix systems, pH independent formulations, bioadhesive forms, low density systems, swelling forms and the like.
The low density systems particularly, float once in contact with the gastric juice and allow prolonged residence time into the stomach by preventing premature emptying through the pylorus. They are usually made of biodegradable materials which disintegrate after a determined period of time and the residual form is then eventually emptied from the stomach. Floating properties of drug delivery systems can be based on several principles, including inherent low density, low density due to swelling or to gas generation.
The swelling systems for example, not only see their size increase above the diameter of the pylorus which results from the unfolding of complex geometric shapes, or the expansion of swellable excipients, but also see their density decrease to provide floating properties. For the gas generating systems, the low density is obtained from the formation of carbon dioxide within the device following contact with body fluids. Some of these dosage forms already exist and usually associate both swelling and gas generation phenomena. Some of them are currently being tested clinically such as Cipro XR®, Xatral® OD, or have already received the approval of a Drug Regulatory Administration such as Glumetza® or Proquin XR®. They however have the draw back not to float directly following the administration, as it takes time for the systems to reach the desired size, and even longer when it is an effervescent form because of the gas generation process.
More advantageously, in inherent low density systems the floating properties are provided since the beginning and swallowing, allowing for substantially no lag time. They are generally provided by entrapment of air, incorporation of low density materials, with foam powders, or combinations thereof. For example, Desai and Bolton in U.S. Pat. No. 4,814,179 developed a moulded agar gel tablet with oil and air, which replaced evaporated water following drying. The process for manufacturing involves the steps of forming an emulsion, from an oily composition of the active and an aqueous solution of agar gel. The emulsion is poured into a mould and subsequently dried. Krögel and Bodmeier proposed in “Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder”, J. Control. Release (1999) 61:43-50, a floating device consisting of an impermeable hollow polypropylene cylinder, containing two drug matrix tablets, each of them closing one end of the cylinder, so that an air-filled space was created in between, resulting in a low density system.
More recently, developments led to single unit and multiparticulate systems containing highly porous polypropylene foam powder and matrix forming polymers, which are said to provide a low density, excellent in vitro floating behaviour and broad spectrum of release patterns. See for example WO 89/06956, disclosing a floating drug wherein a porous structural element, such as a foam or a hollow body is placed within a matrix, and optionally compressed into a tablet dosage form. See also Streubel, Siepmann & Bodmeier, “Floating matrix tablets based on low density foam powder”, Eur. J. Pharm. Sci. (2003) 18:37-45, or Int. J. Pharm. (2002) 241:279-292, which provides examples of such matrix forming polymers: hydroxypropyl methylcellulose, polyacrylates, sodium alginates, corn starch, carrageenan, gum guar, gum arabic, Eudragit®RS, ethyl cellulose, or poly methyl methacrylate.
Another multiple unit gastroretentive drug delivery system containing air compartments was disclosed by lannucelli et al., wherein each single unit consisted of a calcium alginate core, separated by an air compartment formed during a drying step, from a calcium alginate or calcium alginate/polyvinyl alcohol membrane. It is said to show both good in vitro and in vivo buoyancy behaviour and suitable drug release patterns were observed when both the core and the membranes were loaded with a solid dispersion of drug/polyvinylpyrrolidone. Finally, some other bead formulations containing air compartment were developed by incorporation of air bubble and air filled hollow spaces within the system. These are disclosed by Bulgarelli et al., in “Effect of matrix composition and process conditions on casein-gelatin beads floating properties”, Int. J. Pharm. (2000) 198:157-165, and by Talukder et Fassihi, “Gastroretentive delivery systems: hollow beads”, Drug Dev. Ind. Pharm. (2004) 30:405-412. Floating properties however depend on the filling state of the stomach.
Most of the above compositions incorporate air into the dosage form via a specific vehicle, e.g. a prefabricated foam product (e.g. polypropylene foam). Still, the above technical solutions are not applicable to any type of active ingredients, do not accommodate any loading rate, and are difficult to carry out. Thus, there is still a need for another inherent sustained release form which provides improved properties and bioavailability.
Particularly, there is a need for a form that is immediately floating into the gastric juice, in order to avoid any premature emptying through the pylorus as it is the case in the existing swellable forms until they have reached the appropriate size. It should also stay longer into the stomach for a prolonged release of the drug, a better bioavailability and an optimized therapeutic efficiency of the drug. In addition, since many sustained release technologies already exist but are only designed for the administration of specific active ingredients, there is still a need to provide a sustained release form which is suitable for the delivery of different drugs and at different possible concentrations. Finally, considering the complexity of the technology of existing forms, there is still a need for systems that can be easily manufactured at an industrial scale.